Synthesis of vitamin a



Patented Feb. 13, 1945 UNITED STATES PATENT OFFICE SYNTHESIS OF VITAMIN A Nicholas A. Milas, Belmont, Mass, assignor to Research Corporation, New York, N. Y., a corporation or New York I No Drawing. Application March 3, 1942,

Serial No. 433,230

, 3 Claims. (Cl. 260-817) The general object of the present invention is to provide a novel process for the synthetic production of vitamin A and a number of related intermediate products.

The accepted chemical structure of vitamin A is represented by the formula:

B-ionone CH; CH;

HzY-CH! Compound II Other alkali alcoholates advantageously may be used in this condensation provided they are free from alcohols.

The reaction of Equation A is understood to involve two reactions which proceed simultanously or successively, i. e. the combination of the c-ionone and the ethyl chloroacetate form- Compound 11a which reacts with the sodium ethylate yielding Compound II.

, buten-1-al-4, Compound IV, Equation C.

EQUATION B CH1 CH:

OH: H H g H H C=C ---C-COOH KOH Compound 11+ 0 Alcohol BYOB:

Compound HI EQUATION C CH: CH:

CH; H H (i: H Distillation H C=C -C=O+CO, Compound IIH- I H H: CH1

Compound IV Compound IV may be prepared also by condensing, in an ethereal solution, p-ionone with ethyl dichloroacetate (C12CHCOOC'2H5) in the presence of dilute magnesium amalgam, yielding Compound IIa, Equation D, which latter may be saponified with alcoholic potash and the resulting saponification product decarboxylated to Product IV as in Equations B and C.

EQUATION D CHI CHI CHI l H CHI Compound Ho Here it will be seen that Compound 11a is identical with the intermediate product of Equation A and when this Product He is subjected to saponification with alcoholic KOH as in Equation 13, it is simultaneously or successively converted into Compound II and Compound III.

Instead of decarboxylating Compound III by distillation as described above, Compound III is mixed with two molecular equivalents of pyridine and the resulting pyridine salt distilled under a pressure of about 1 mm. and the fraction distilling at about C. to 103 C. (Compound IVa) collected. This fraction (Compound IVa) serves in the remainder of the process described hereinafter in the same way as Compound IV but evidence, such as its boiling point, spectroscopio examination, and absence of aldehydic properties, indicates that it is not Compound IV but a compound of the formula CH; CH;

H H H H C=C -CE W O Hy-Ch;

CompoundIVu impure state and may be purified either by high vacuum distillation in an inert atmosphere or by preparing its phthalic acid ester by reacting the mixture with phthalic anhydride in pyridine solution. The phthalic acid ester is subsequently saponifled to obtain the pure acetylene carbinols, Compound V or Compound Va.

EQUATION E CH] CH C lnliIlgid H C C a Ha H Compound V EQUATION EA CH1 CH1 Compound IV+ NaCECH H in liquid NH;

Compound IVo Compound Va It will be observed that Compounds V and Va are identical excepting that the positions of the hydrogen atom and the hydroxyl group on the third and fourth carbon atoms of the side chain counting from left to right are reversed.

Compound V or Compound Va may be prepared also (see Equation F) by the interaction of the mono-Grignard of acetylene (HCECMgX) and Compound IV or Compound IVa, respectively.

EQUATION F HCECMgX O! 0] Compound 1V1: (X stands for halogen) Compound Va In the fourth step, Compound V or Va may be dehydrated by distilling under high vacuum with small amounts of naphthalene sulfonic acid or p-toluene sulfonic acid yielding Compound VII directly (see Equation G).

Compound IV Compound V EQUATION G Compound V compgi znd Va distillation dehydrating catalysts Thus it will be seen that both Compounds IV and We may be treated in the same manner to yield Compound VII.

vacuum Compound VII (see Equation 1) However, better yields of Compound VII are obtained by preparing from Compounds V and Va the halides thereot, Compounds VI and VIa, Equations H and Ho, and subsequently removing hydrogen halide with alcoholic potash (see Equations I and la) EQUATION H CHI CHI PX: Compound V+ --o Pyridine iil) which X is a halogen) Compound VI EQUATION HA CH: CH1 CH1 H H H PX: H C=C -(CECH Compound Vo+ I H Pyridine X [in which X is a halogen) Compound Vla It is observed that Equation Ha works best with the chloride, less well with the bromide, and poorly or not at all with the iodide.

EQUATION I CHI CH] OH:

H H H KOH H C=C =C-CECH Compound VI+ alcohol Cu mpound V! I EQUATION IA KOH Compound VIu+ -v Compound VII alcohol Still another method of converting Compound V or Compound Va into Compound VII is to form the Grignard of Compound V having the-formula CH3 CH:

OH: H

Grignurd of Compound V (X stands ior halogen) or the Grignard of Compound Va having the formula Grianord 0] Compound V1:

(X stands for halogen) and mix either of said Grlgnard compounds with exactly one moi of CH: HO-C -CH:

and distill the mixture under a high vacuum. I

In the fifth step the Grignard or alkali metal acetylide of Compound VII is prepared by allowin; it to react in ether solution with ethyl maznesium bromide or metallic lithium, for example: To the Grignard or alkali acetylide of Compound VII is slowly added methyl vinyl'ketone A} 11 c=cm) whereby the Product VIII is formed (see Equation J).

In the sixth step Compound VIII is partially hydrogenated catalytically at room temperature using gaseous hydrogen and palladium black catalyst deposited on calcium carbonate or barium sulfate yielding Compound IX, Equation K. Another useful method for the partial reduction of Compound VIII to produce Compound IX is the use 01' an active iron catalyst. made by leaching with alkali the aluminum from an aluminumiron alloy, and hydrogen under a pressure of about -75 atmospheres and temperatures not higher than 100 C. (see Equation K).

EQUATION K HI Compound VIII+ Pd or active iron CH1 CH:

\ CH: OH

H H J: H H H H H C=C =C-C=C- O=CH:

| H H CH3 Compound IX In the seventh step, Compound IX may be treated with acetic anhydride to form the acetic ester of vitamin A, Compound XI, Equation L.

In this step any suitable acid anhydride other than acetic anhydride, such as propionic and its higher homologue-s up to and including palmitic and stearic and other organic acid anhydrldes, such as benzoic acid anhydride, could be employed to produce the corresponding vitamin A esters, any of which may be converted into vitamin A by saponiflcation, as described hereinafter.

EQUATION L acetic anhydride Compound IX+ Compound XI (See Equation N) Better yields of the acetate are obtained when Compound IX is treated first with a halogenating agent such as phosphorus tribromide in pyridine yielding Compound X, Equation-M, which latter is treated with potassium acetate yielding Compound XI, Equation N.

In this step Compound IX may be treated with any other suitable haiogenating agent such as phosphorus trichlorideor thionyl chloride and the resultins halogen Compound X converted into any desired organic acid ester of vitamin A by treating it with the alkali metal salt of the desired acid in the presence or the free acid.

Still another method 01' making the esters of vitamin A is to treat Compound XV or Compound xva with acetic or any other suitable organic acid anhydride in the presence of the alkali metal salt oi said acid and heat the mixture in vacuum thereby directly producing the acid ester of vitamin A.

EQUATION M Compound 1x+ -u (in which X stands for halogen) Compound X Eom'non N Potassium acetate CHI H H I Compound XI The vitamin is finally prepared by saponifying Compound XI, Equation 0, or by treating Coma pound X with silver hydroxide (see Equation P).

Eouanou O saponiiy alcoholic KOH oil-70 C. in Na atmosphere EQUATION P ABOH -O in alcoholic solution up to 50 C. In the preparation of Compound XI, the following alternative route may be used: Methyl vinyl ketone is condensed with sodium or lithium acetylide in liquid ammonia to produce Compound XII, Equation Q, which latter is then converted into the Grignard XIII, Equation R, by interaction with ethyl magnesium bromide. The Girlsnard XIII is allowed to react in ether solution with the Compound IV or IVa followed by hydrolysis with tartaric acid or ammonium sulfate to produce Compound XIV or XIVa, Equation 8 or 80.

Compound XI+ Compound I Compound X+ Compound I EQUATION Q CH: OH: H ([3 HCECNa H g: 6 H:C=C- =0 H|C=C- CECH in liquid N El Compound XII EQUATION R CH:

2C1HsMgX H 1: Compound XII H:C=C -CECMgX (X stands for halogen) MgX Compound XIII Eommoa 8 followed by hydrolysis with Compound IV Compound XIII --o tartarlc acid (NHOQSO.

CHI CH:

on: on; J: n A H H n c=c -c-c5c -c=c H a a H HYCHz 10 Compound XIV 0 (UV +0 axm Mona by m ill) em 1111 0 Do u m hydrolysls CHI CH; cm on.

H H L n L H n H o=c- =g-czc- :=3

K H: CH: H

Compound XIVo Compound XIV or XIVa is then partially reduced to Compound XVor XVa using the catalysts and conditions described above (see Equations T and Ta) EQUATION T c dXIV+ o em on p0 Pd on C8001 or BaSOi CH: CH: CH: CH:

H H 1 H H H L H n o=c o=o- -o=cm i l H H H CHI Compound IV Earn-non TA Ha Compound XIVa+ ---o catalyst on. on, on. on.

H H H H H l H n -c=c-- -oc=0- -c=cn,

H H CH: H

Compound X Va An alternative method used to prepare Com- Pound XIV or XIVa consists in the interaction of the Grignard of V or Va with methyl vinylketone (see Equations U and U11) EQUATION U Grignimi of V on CH on. on. 50

H H (E H (l: H C=CHCCEGMgX+O= -cn=cn,- xrv ikMgX H CH:

(X stands for halogen) E UATION Us Grlonord :1 Va CHI CHI CH; CHI 7 H H n 1 n\ c=o- -%-czcMx +o= oH=oH.- xIv Hay-CH: LMgX (X stands [or halogen] Compound XV or xVa is halogenated with a suitable agent such as a phosphorus trlhalide, e. g. phosphorus trichloride or tribromide in pyridine at 0 C. yielding Compound XVI or xvm, Equations W and We, and the latter are dehydrohalogenated, for example, by treating with exactly one mol of potassium hydroxide in alcohol to yield Compound X, Equation Y.

Equarron W Pyridine H at 0 C.

H OH:

I Compound XVI (In whlcbxstandllorbalogenl Ecua'noir WA CH: CH; CH; CH: PX; H H L H H H L H XVu+ -o H C= CC==C- =C-CHX Pyridine H atll 1 (inwhichxstandslorbalogen) (impound XVIl (The above reactions work better with the chloride than with the bromide.)

EQUATION Y A more detailed account of the principal reactions is to be found in the following pages.

KOH Compound 1 alcohol PREPARATION or GLYCIII EsTsa Cor-mom 11, FIRST Bur, EQUATION A Twenty-four grams of metallic sodium is dissolved in about 300-400 cc. O1 absolute ethyl alcohol in a one liter filter flask fitted with a reflux condenser. It has been found preferable to add all of the sodium at once and after it had gone into solution, the alcohol is removed under reduced pressure at temperatures ranging from 160-170". A white sodium ethylate results. This is added slowly to a vigorously stirred mixture of 192 grams of p-ionone, 122 grams ethyl chloroacetate and 110 cc. of anhydrous toluene (benzone may also be used) at 0. After all of the sodium ethylate had been added, stirring is continued until the mixture becomes homogeneous and brownish in color, then allowed to stand at room temperature for 7-10 hours. It is then heated on the water bath for 5 hours, cooled to room temperature and acidified with 25% acetic acid. The oil separating from this mixture is fractionated under reduced pressure and the fraction boiling at 152-155 (2-3 mm.) collected. A yield of about of Compound II is obtained.

PREPARATION or Compomms III AND IV, Scconn STEP, Eons-nous 3 am) C To obtain Compound III, 107 g. of Compound II is mixed with one equivalent (21.6 g.) of 10% alcoholic potash and the mixture heated on the water bath for about two hours. The alcohol is then removed under reduced pressure an the residue dissolved in th minimum amount of water and the aqueous mixture extracted a few times with ether to remove any unsaponiiiable matter. The aqueous solution is then treated with 25% phosphoric acid and the oily layer which separates extracted with ether. The ether extract is then dried with anhydrous magnesium sulfate, filtered and the ether removed under reduced pressure. The residue (Compound III) is heated in an atmosphere of nitrogen and in the presence oi powdered glass or finely divided copper to facilitate the removal of carbon dioxide and the aldehyde formed finally fractionated under reduced pressure and the traction boiling at 143-145 min.) collected. This has an 11,," 1.5032 and forms a 2,4-dinitrophenylhydrazone; M. P. 155-157 having the correct combustion analysis.

This aldehyde (Compound IV) has also been prepared by the alternative method (Equation D) described as part of the second step.

The preparation of Compound Iva from Comound III by reaction with pyridine and distillation has been sumclently described above.

BIO CH:

Cbmpound IVa To a mixture oi 245 g. (2 mols) o1 ethyl chloroacetate and 110 g. of anhydrous, sulfur-tree toluene contained in a three-necked, round-bottomed flask equipped with a mercury-sealed stirrer, a thermometer, and a calcium chloride tube and cooled to about 35' add 192 g. (1 mol) oi p-ionone. By means 01' a Gooch rubber connection introduce, over a period of two hours with rapid stirring, 46 g. (2 mole) of finely powdered sodium ethoxide tree from alcohol. Bring the mixture slowly to room temperature by allowing it to stand overnight with moderate stirring in an atmosphere of nitrogen. Continue stirring while the mixture is heated in nitrogen on the water bath for four hours, then coolto room temperature and neutralize with a solution of 167 g. of glacial acetic acid in 500 cc. of water. The mixture separates into two layers. Remove the non-aqueous layer and extract the aqueous layer with two 50 cc. portions of ether and combine the extracts with the non-aqueous layer. Remove the ether and the toluene and other low boiling constituents by subjecting the mixture to a vacuum distillation (-20 mm.) in an atmosphere of nitrogen at the temperature of boiling water. Cool the residue (Compound 11) to room temperature and add to it 840 cc. or 95% alcohol containing 85 g. of potassium hydroxide and reflux the resulting mixture in nitrogen ior one hour under a slightly reduced pressure, then remove under reduced pressure approximately twothirds oi the alcohol. Cool the residue and pour it into 1500 cc. of deoxygenated water and extract the mixture successively with 500, 200 and 150 cc. of ether: combine the extracts and wash with 200 cc. or water and combine the latter with the aqueous solution. Add to the aqueous layer 200 cc. of fresh ether and acidity with 654 cc. of orthcphosphoric acid. Remove ether layer and extract non-aqueous layer successively with 200 and 100 cc. oi ether and combine ether extracts wash ether extracts twice with 110 cc. portions or water, dry over anhydrous magnesium sulfate.

. filter and remove ether under reduced pressure.

The residue consists oi almost pure glycidlc acid (Compound 111) containing small amounts 01' ethoxy acetic acid.

To decarboxylate the gLvcidic acid dissolve it in 158 g. (2 mole) of pure anhydrous pyridine and subject the mixture to a vacuumjistillation in an atmosphere of nitrogen. The pyridine comes over at lower temperatures, then. the residue is iractionated and the fraction boiling at 95-140 (2 min.) is collected and designated as the crude portion 01 Compound Iva. This product is round to contain a small amount or an organic acid, and to remove the latter the product is dissolved in 250 cc. of ether and the ethereal solution shaken vigorously twice with 200 cc. oi 5% sodium bicarbonate solution. The ethereal solution is then dried over magnesium sulfate, filtered, the ether removed under reduced pressure and the residue fractionated using a Claisen flask attached to a 30 cm. Vigreux column and the fraction boiling at -103 (1-2 mm.) collected. no 1.5110. dis- 0.040. This product rails to give an aidehyde test with iuchsin reagent and absorption spectrum in the ultra-violet region or the spectrum fails to show the presence or an aldehyde group either isolated from or conjugated with the double bonds.

The large range in boiling point (90-103) indicates the presence in the product or the cis and trans isomers. The boiling point 01' the major isomer is about 99 to 103.

PREPARATION or Couroimns V sap Vs. Tmnn Srnr, Equsrrons E 1mm Es To about 1 l. of liquid ammonia. in a. 3-necked flask equipped with a Hershberg stirrer and a dropping iunnel, was added 1 g. 01 hydrated ferric nitrate and 1 g. oi metallic sodium and the mixture stirred for 1 hour wlule the temperature was kept at -o5" to -70. To this mixture was then addeda trifle excess over half a mol of metallic sodium and the mixture stirred for half an hour longer. Dry acetylene was then passed through the mixture for several hours or until most of the blue color had assumed a grayrwhite color. To this mixture was then added, in the course of three hours, 46 g. of Compound IV or Compound Na in 200 cc. of anhydrous ether taking care that the temperature 01 the mixture never rises above --60 and that the stirring is very rapid. After all of the aldehyde or oxide had been added, the mixture is stirred for 24 hours longer, keeping the temperature between -55 M and 70". The ammonia is then allowed to evaporate and the brownish residue treated with excess cold aqueous solution or d-tartaric acid and the resulting mixture extracted with ether from which the acetylene carbinol. Compound V or Compound Va, is isolated either by distillation under high vacuum (10* mm.) or by preparing its acid phthalate ester in anhydrous pyridine and subsequently saponifying this ester to obtain the pure acetylene carhinol. The phthalic acid ester had the correct analysis and semi-micro-hydrogenation revealed the presence of 4 double bonds. The acetylene carbinol also gives a heavy whitishgray precipitate with ammoniacal alcoholic silver nitrate solution characteristic for acetylenes.

Compounds V and Va have also been prepared. in anhydrous ether solution, by the interaction of Compounds IV and IVa, with the mono-Grignard of acetylene (HCaCMgX) (Equation F) Pssrsasrron orcourounnsvlvismvfl, FounmSrxr,EousrroxsH,HssnnImIs Five 8. about 15 g. of ture cooled between ture is slowly added about of standing at 0, the mixture 60-70 for 15 minutes. then. without separating CompoundVIorVIa,themixtureistreatedwith the calculated amount plus 10% excess of 10% alcoholic potash. The mixture is heated on the waterbathforhalianhounthenpouredinfmir times its volume of water. The aqueous mixture is extracted several times with ether and the ethereal solution shaken a number of times with a solution of d-tartaric acid to remove the pyridine. Finally, the ether solution is dried over anhydrous magnesium sulfate, filtered, and the ether removed. The residue is nearly ure Compound VII, although for further purification one can distillltimderavery 1118 7 Compound VII may also be prepared by distillingconmoundvorvounderreducedpressure (1o=-1o-= mm.) in the presence of small amoimts, 1 to of p-toluene sullonic acid or naphthalene sulionic acid (Equation (3).

Pssrsasrron or Couroulm VlIl, Frrrn Srsr, EQUATIOI J Five g. of Compound VII in 30 cc oi anhydrous ether is slowly added to an ethereal solution of the calculated amount of ethyl magnesium bromide and the mixture refluxed in an atmosphere of nitrogen for 5 to hours. To this mixture is then slowly added at 0 with stirring about 2 g. of methyl vinyl ketone whichis freshly distilled from small amounts of hydroquinone. The mixture is allowed to stand at room temperature overnight, then poured onto a mixture of ice and ammonium sulfate. After the Grignard mixture is completely hydrolyzed, the ethereal layer is separated and dried over anhydrous magnesium sulfate, filtered, and the ether removed under reduced pressure. The residue which is nearly pure Compound VIH may now be used for the next step.

For making Compound VIII from Compound VII viathe alkali metal acetylide of Compound VII instead of the Grignard thereof, a mixture of equal parts of liquid ammonia and anhydrous ethyl ether is prepared and while being maintained at 60 to -'l0 C. small equivalent amounts of Compound VII dissolved in anhydrous ethyl ether and metallic lithium are added while rapidly stirring. After each addition, the blue color produced is permitted to completely disappear before another addition of Compound VII and lithium is made. After the desired amount of Compound VII and the equivalent amount of lithium have been dissolved, a solution of an equivalent quantity of methyl vinyl ketone in anhydrous ethyl ether is added dropwise, in the course 01' an hour, with continued stirring and while maintaining the temperature at 60 to -'70 C. The stirring and maintenance of the temperature of -60 to -'l0 C. is then continued for about 10 hours, after which the temperature is allowed to rise and the ammonia to evaporate. The reaction mixture is then neutralized with tartaric acid dissolved in ice cold water and the resulting mixture extracted several times with ethyl ether. The combined ether extracts are anhydrous sulfate. then illtered.tbeetherevanorated1mderreducedpressureandtheresiduesubiectedtoavacuumoi noml0- to10- mmofmercurytovaporizeand Compoimd VIII is dlmolved in absolute alcohol one-twentieth oi pureIx.

'lhereducflonofcomlio dvmmcnm d lXmayalsobeaccmnpllshedunderw-fiatmosm fhydrogenatnothiaherthanlou'c. n in the presence of an active iron catalyst mm byleacmngtherrmnanirmaluminumalloy (EquatlonKl.

Plumrronorcollroulnnslvnmfirlr, Equsrronsllsnnfl AlthoughCompoundXImaybepreparedby the treatment of Compound 13 with acetic anhydrlde (Equation L) better yields are obtained by dissolving Compound xx in anhydrous pyridine, cooling to 0, and adding the calculated amount of phosphorus tribromide, Equation 1!, takingcarethatthetemperaturedoesnotrise above 0''. The mixture is then warmed to room temperature and kept there for two hours. The mixture is then dissolved in ether and the ethereal solution extracted with a cold 25% solution of acetic acid to remove the pyridine and the phosphorous acid. After the ethereal solution is dried over anhydrous magnesium sulfate, and filtered, the ether is removed under reduced pressure and the residue Compound X, Equation M, is dissolved in glacial acetic acid and treated, in an atmosphere of nitrogen, with freshly fused potassium awtate, Equation N. The mixture is gently heated for about 2 hours to not higher than C., then poured in cold water and extracted with ether. The ethereal solution is separated, dried, and the ether removed. The residue contains considerable amount of Com pound XI from which vitamin A can be easily prepared by saponifylng it in the usual manner with alcoholic potash (Equation 0). However, Compound XI may be used directly as a vitamin A substitute.

This application is a continuation-in-part of my application Serial No. 353,775, filed August 22, 1940.

I claim:

1. As a new product a compound of the forformula CHI OH; H H H H C=C- I ?CEC- C=C I Y Y an H CH:

wherein one Y represents H and the other Y rep- 3. As a. new product a compound of the formula. resents cm cm OH: on.

2. As a. new product a compound of the formula CHI 11 0Ec-tL-- =CH: H H H L H 5 i H H n c=oc-czc- -c=oH, H cg, (an H n cm NICHOLASA. MILAB.

- 7 CERTIFICATE OF comcnon. Patent No. 2,569,16h. February 1 1915.

NICHOLAS A. nuns.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: PageT, first column, line 10, claim 2, for the lowermost portion of the fonnula read-- ing H reed -=H -;end that the said, Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 26th day of June, ALD. 1915.

Leslie Frazer (Seal) Acting Commissioner of Patents.

wherein one Y represents H and the other Y rep- 3. As a. new product a compound of the formula. resents cm cm OH: on.

2. As a. new product a compound of the formula CHI 11 0Ec-tL-- =CH: H H H L H 5 i H H n c=oc-czc- -c=oH, H cg, (an H n cm NICHOLASA. MILAB.

- 7 CERTIFICATE OF comcnon. Patent No. 2,569,16h. February 1 1915.

NICHOLAS A. nuns.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: PageT, first column, line 10, claim 2, for the lowermost portion of the fonnula read-- ing H reed -=H -;end that the said, Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 26th day of June, ALD. 1915.

Leslie Frazer (Seal) Acting Commissioner of Patents. 

